Trends in Biochemical Sciences
Structure, mechanism and regulation of peroxiredoxins
Section snippets
Dimers, decamers and redox-dependent oligomerization
The first reports of Prx oligomerization came in the late 1960s, when transmission electron microscopy (TEM) studies of torin, an abundant protein isolated from human erythrocytes, revealed discrete complexes with apparent tenfold symmetry (Fig. 2a) [30]. Later, in the 1980s, bacterial and yeast Prxs were identified based on their antioxidant properties 31, 32. Torin has since been identified as mammalian PrxII, a typical 2-Cys Prx [33]. In the TEM reports, it was observed that under certain
The Prx classes have similar active sites
Since 1998, the crystal structures of six Prxs have been published, including four typical 2-Cys Prxs (PrxI, PrxII, TryP and AhpC 19, 20, 21, 22), one atypical 2-Cys Prx (PrxV [27]) and one 1-Cys Prx (PrxVI [17]) (Fig. 3). These structures reveal Prxs to be very similar, each containing a thioredoxin fold with a few additional secondary-structure elements present as insertions. The most striking differences involve their oligomeric states. The atypical 2-Cys Prxs are monomeric enzymes, whereas
Catalytic cycle for typical 2-Cys Prxs
Some typical 2-Cys Prxs from bacteria 15, 34 (L.B. Poole, unpublished) and human and rat PrxII 13, 27 undergo redox-sensitive oligomerization. These studies revealed that the reduced or overoxidized forms of the enzyme favored the decameric state, whereas the disulfide-bonded forms existed predominantly as dimers. The current ensemble of Prx structures forms the basis of a detailed catalytic cycle that includes the redox-sensitive oligomerization of these 2-Cys Prxs [22], although the precise
Regulation of Prx activity
Prxs have received a great deal of attention recently owing to their role in regulating levels of hydrogen peroxide, an intracellular signaling molecule common to many cytokine-induced signal-transduction pathways 3, 8, 12, 13. As noted above, some Prxs are themselves sensitive to inactivation by hydrogen peroxide and perhaps peroxynitrite through irreversible oxidation of their peroxidatic cysteine. Indeed, regulation of redox signaling through cysteine modification by peroxides and
Conclusions
The ubiquitous Prxs appear to be diverse in function, ranging from antioxidant enzymes to regulators of signal transduction. This diversity is reflected in slight evolutionary modifications in sequence and structure, built around a common peroxidatic active site. The literature within the Prx field is currently focused on their more recently identified roles as regulators of redox-sensitive signaling 3, 8. Although the precise relationship between the peroxidase activity and the oligomeric
Acknowledgements
We thank S. Watabe for the gift of bovine mitochondrial PrxIII used in Fig. 2d and M. Isupov for preparation of Fig. 2c. We also thank P.A. Karplus for helpful discussions. Structural work on bacterial Prxs in the Poole and Karplus laboratories is supported by a grant from the US National Institutes of Health (GM-50389). A grant from the Stiftung Innovation von Rheinland-Pflaz (GZ. 8312–386261/281) to J.R.H. is also acknowledged. L.B.P. is an Established Investigator with the American Heart
References (56)
Thioredoxin-dependent peroxide reductase from yeast
J. Biol. Chem.
(1994)An alkyl hydroperoxide reductase from Salmonella typhimurium involved in the defense of DNA against oxidative damage. Purification and properties
J. Biol. Chem.
(1989)- et al.
Oxidation of active center cysteine of bovine 1-Cys peroxiredoxin sulfenic acid form by peroxide and peroxynitrite
Free Radic. Biol. Med.
(2001) - et al.
Peroxiredoxins in cell signaling and HIV infection
Reconstitution of Ca2+-dependent K+ transport in erythrocyte membrane vesicles requires a cytoplasmic protein
J. Biol. Chem.
(1991)Characterization of three isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin
Diabetes Res. Clin. Pract.
(1999)Crystal structure of decameric 2-Cys peroxiredoxin from human erythrocytes at 1.7 Å resolution
Structure
(2000)The structure of reduced tryparedoxin peroxidase reveals a decamer and insight into reactivity of 2Cys-peroxiredoxins
J. Mol. Biol.
(2000)Identification of a new type of mammalian peroxiredoxin that forms an intramolecular disulfide as a reaction intermediate
J. Biol. Chem.
(2000)Crystal structure of human peroxiredoxin 5, a novel type of mammalian peroxiredoxin at 1.5 angstrom resolution
J. Mol. Biol.
(2001)
Phospholipid hydroperoxides are substrates for non-selenium glutathione peroxidase
J. Biol. Chem.
Cyclophilin A binds to peroxiredoxins and activates its peroxidase activity
J. Biol. Chem.
Some negative contrast staining features of a protein from erythrocyte ghosts
J. Mol. Biol.
Positive control of a regulon for defenses against oxidative stress and some heat-shock proteins in Salmonella typhimurium
Cell
The isolation and purification of a specific protector protein which inhibits enzyme inactivation by a thiol/Fe(III)/O2 mixed-function oxidation system
J. Biol. Chem.
Comparison of the decameric structure of peroxiredoxin-II by transmission electron microscopy and X-ray crystallography
Biochim. Biophys. Acta
Porcine natural-killer-enhancing factor-B: oligomerisation and identification as a calpain substrate in vitro
Biochim. Biophys. Acta
Cloning, over-expression and characterization of peroxiredoxin and NADH–peroxiredoxin reductase from Thermus aquaticus YT-1
J. Biol. Chem.
Properties of thiol-specific anti-oxidant protein or calpromotin in solution
Biochem. Biophys. Res. Commun.
Calcium-induced erythrocyte membrane changes. The role of adsorption of cytosol proteins and proteases
Biochim. Biophys. Acta
Calcium-activated potassium transport and high molecular weight forms of calpromotin
J. Biol. Chem.
Tryparedoxin peroxidase of Leishmania donovani: molecular cloning, heterologous expression, specificity and catalytic mechanism
Arch. Biochem. Biophys.
Variants of peroxiredoxins expression in response to hydroperoxide stress
Free Radic. Biol. Med.
Regulation of thioredoxin peroxidase activity by C-terminal truncation
Arch. Biochem. Biophys.
Proteomics analysis of cellular response to oxidative stress: evidence for in vivo over-oxidation of peroxiredoxins at their active site
J. Biol. Chem.
Regulation of peroxiredoxin I activity by Cdc2-mediated phosphorylation
J. Biol. Chem.
Routine preparation of air-dried negatively stained and unstained specimens on holey carbon support films: a review of applications
Micron
Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes
Proc. Natl Acad. Sci. USA
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